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Updated Analysis From KEYNOTE-189:
Pembrolizumab or Placebo Plus Pemetrexed and
Platinum for Previously Untreated Metastatic
Nonsquamous Non
–Small-Cell Lung Cancer
Shirish Gadgeel, MB, BS1; Delvys Rodr´ıguez-Abreu, MD2; Giovanna Speranza, MD, MSc3; Emilio Esteban, MD4;
Enriqueta Felip, MD, PhD5; Manuel D ´omine, MD, PhD6; Rina Hui, MB, BS, PhD7; Maximilian J. Hochmair, MD8; Philip Clingan, MB, BS9; Steven F. Powell, MD10; Susanna Yee-Shan Cheng, MD11; Helge G. Bischoff, MD12; Nir Peled, MD, PhD13; Francesco Grossi, MD14; Ross R. Jennens, MB, BS15; Martin Reck, MD16; Edward B. Garon, MD17; Silvia Novello, MD, PhD18; Bel ´en Rubio-Viqueira, MD19; Michael Boyer, MB, BS, PhD20; Takayasu Kurata, MD, PhD21; Jhanelle E. Gray, MD22; Jing Yang, PhD23; Tuba Bas, PhD23; M. Catherine Pietanza, MD23; and Marina C. Garassino, MD24
abstract
PURPOSEIn KEYNOTE-189,first-line pembrolizumab plus pemetrexed-platinum significantly improved overallsurvival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680).
METHODS Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab
(n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis.
RESULTSAs of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was
22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurredfirst (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed re-gardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups.
CONCLUSION First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially
improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.
J Clin Oncol 38:1505-1517. © 2020 by American Society of Clinical Oncology
INTRODUCTION
Until the advent of immunotherapy,first-line treatment of patients with advanced nonsquamous non ‒small-cell lung cancer (NSCLC) without anEGFR/ALK alter-ation was platinum-based chemotherapy, with addition of bevacizumab as an option in select patients.1,2The introduction of pembrolizumab, an anti‒programmed death-1 (PD-1) monoclonal antibody, has altered the treatment paradigm for patients with NSCLC. Pem-brolizumab has shown efficacy in first-line therapy of advanced/metastatic NSCLC both when administered as monotherapy in patients with programmed
death-ligand 1 (PD-L1) tumor proportion score (TPS)$ 50%3 and$ 1%4 and when administered in combination with platinum-based chemotherapy regardless of tumor PD-L1 expression.5-7 In an analysis of the randomized, double-blind, phase III KEYNOTE-189 study conducted with a median follow-up of 10.5 months, pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS; hazard ratio [HR], 0.49; 95% CI, 0.38 to 0.64; P , .001), progression-free survival (PFS; HR, 0.52; 95% CI, 0.43 to 0.64;P , .001), and objective response rate (ORR; 47.6%v 18.9%; P , .001) compared with placebo plus pemetrexed-platinum in patients with ASSOCIATED CONTENT Data Supplement Protocol Author affiliations and support information (if applicable) appear at the end of this article. Accepted on February 4, 2020 and published at ascopubs.org/journal/ jcoon March 9, 2020: DOIhttps://doi.org/10. 1200/JCO.19.03136
metastatic NSCLC without sensitizingEGFR/ALK alterations, regardless of PD-L1 TPS.6Toxicity with pembrolizumab plus pemetrexed-platinum was manageable.
In this updated analysis from KEYNOTE-189, we evaluated efficacy and safety with approximately 10 additional cal-endar months of follow-up from the first interim analysis data cutoff date. Extrapulmonary metastases to sites such as the liver and brain frequently occur in metastatic NSCLC and are associated with a poor prognosis8,9; whether such metastases alter the magnitude of benefit with immuno-therapy has been uncertain.10 Therefore, we assessed outcomes among patients with liver/brain metastases. Finally, to characterize the treatment effect of pembrolizumab on the next line of therapy, we conducted a protocol-specified ex-ploratory analysis of progression-free survival-2 (PFS-2).11 METHODS
Patients and Study Design
The study design has been previously described.6Briefly, patients had previously untreated pathologically confirmed metastatic nonsquamous NSCLC without sensitizingEGFR/ ALK alterations, Eastern Cooperative Oncology Group performance status of 0/1, and$ 1 measurable lesion, and provided a tumor sample for PD-L1 evaluation. Exclusion criteria included symptomatic CNS metastases, history of noninfectious pneumonitis requiring glucocorticoids, active autoimmune disease, or systemic immunosuppressive therapy. All patients provided written informed consent; study procedures were approved by an independent ethics committee at each site. Patients were randomly assigned (2:1) to receive either 200 mg pembrolizumab or saline placebo every 3 weeks for up to 35 cycles. Randomization was stratified by tumor PD-L1 TPS ($ 1% v , 1%), choice of platinum (cisplatinv carboplatin), and smoking history (neverv former/current). All patients received pemetrexed and investigators’ choice of cisplatin or carboplatin every 3 weeks for 4 cycles followed by pemetrexed maintenance therapy every 3 weeks. Patients who received placebo could cross over to pembrolizumab monotherapy at the time of disease progression (as verified by a blinded, in-dependent central radiologic review [BICR]) if they met eligibility criteria.
Assessments
Tumor tissue samples obtained by core-needle or exci-sional biopsy at the time of diagnosis werefixed in formalin and centrally assessed for PD-L1 expression using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA). PD-L1 expression was categorized by TPS (the percentage of tumor cells with membranous PD-L1 staining). Tumor imaging occurred at weeks 6 and 12, every 9 weeks through week 48, and every 12 weeks after week 48. Patients with brain metastases underwent im-aging of the brain at the same intervals. Response was assessed per RECIST (version 1.1) by BICR. Survival was
assessed every 12 weeks after discontinuation of study treatment. Adverse events (AEs), including AEs of special interest, through 30 days (90 days for serious AEs) after the last treatment dose or until start of new therapy were graded according to the National Cancer Institute–Common Ter-minology Criteria for Adverse Events (version 4.0). Endpoints
The dual primary endpoints were OS and PFS; secondary endpoints were ORR, duration of response (DOR), and safety. Efficacy analyses in patients with baseline liver or brain (prespecified) metastases were exploratory. PFS-2, which was defined as the time from randomization to objective tumor progression on next-line treatment (in-cluding subsequent anti‒PD-[L]1 therapy) or death from any cause, whichever occursfirst, was a protocol-specified exploratory endpoint. Events for PFS-2 analysis were characterized as time of investigator-assessed disease progression that led to cessation of second-line therapy, start of third-line therapy for patients who stopped second-line therapy without disease progression, and time of death for patients who either stopped second-line therapy without disease progression and did not initiate third-line therapy or did not receive second-line therapy. Patients were cen-sored for PFS-2 at the time of last known survival if they were alive and either had not received second-line therapy or had stopped second-line therapy without disease pro-gression and had not initiated third-line therapy.
Statistical Analyses
Efficacy analyses were performed in the intention-to-treat (ITT) population, which included all randomly assigned patients; safety analyses were performed in the as-treated population, which included all randomly assigned patients who received $ 1 dose of therapy. The Kaplan-Meier method was used to estimate OS, PFS, and PFS-2. A stratified Cox proportional hazards model with Efron’s method of tie handling was used to determine HRs and 95% CIs. Stratification factors used for randomization were applied. Analyses were not controlled for multiplicity; no alpha was assigned to this updated analysis.
RESULTS
Patients and Treatments
Overall, 616 patients were randomly assigned to pem-brolizumab plus pemetrexed-platinum (n = 410) or placebo plus pemetrexed-platinum (n = 206). Patient demographics and baseline disease characteristics were generally similar between groups (Table 1). The proportions of patients in
PD-L1 TPS subgroups (, 1%, 1%-49%, and $ 50%) were
similar between treatment groups; approximately one third of patients had TPS, 1%. At baseline, 66 (16.1%) and 73 (17.8%) patients in the pembrolizumab-combination group had liver and brain metastases, respectively, versus 49 (23.8%) and 35 (17.0%), respectively, in the placebo-combination group.
At data cutoff (September 21, 2018), median (range) study follow-up (time from randomization to database cutoff) was 23.1 (18.6 to 30.9) months, and median (range) time from randomization to death or database cutoff, whichever oc-curredfirst, was 18.7 (0.2 to 30.9) months. Mean (standard deviation) treatment duration was 9.8 (7.8) months in the pembrolizumab-combination group and 6.2 (5.7) months in the placebo-combination group (Data Supplement, online only). In the pembrolizumab-combination group, 58 patients (14.1%) remained on $ 1 component of study therapy compared with 7 patients (3.4%) in the placebo-combination group (Fig 1). An additional 58 patients (14.1%) in the pembrolizumab-combination group and 8 patients (3.9%) in the placebo-combination group had stopped all study treatment and were alive without sub-sequent treatment, including 36 (8.8%) and 4 (1.9%), respectively, who were without disease progression. Twenty-four patients in the pembrolizumab-combination group and 1 in the placebo-combination group completed 35 cycles of pembrolizumab or placebo, respectively; 12 patients remained on pemetrexed only (all in pembrolizumab-combination group). In the ITT population, 183/410 pa-tients (44.6%) in the pembrolizumab-combination group and 122/206 (59.2%) in the placebo-combination group
received$ 1 subsequent therapy; 84 patients (40.8%) in the placebo-combination group crossed over on-study to pembrolizumab monotherapy, and 111 received any sub-sequent anti–PD-(L)1-therapy (effective crossover rate, 53.9%; Data Supplement).
OS and PFS
At the time of data cutoff, 213 patients (52.0%) in the pembrolizumab-combination group and 144 patients (69.9%) in the placebo-combination group had died. Median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group and 10.7 (8.7 to 13.6) months in the placebo-combination group (HR, 0.56; 95% CI, 0.45 to 0.70; Fig 2A); estimated 24-month OS rates were 45.5% and 29.9%, respectively. The addition of pembrolizumab provided survival benefit irrespective of PD-L1 expression (Figs 2B-2D); Data Supplement).
Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months in the pembrolizumab-combination and placebo-combination groups, respectively (HR, 0.48; 95% CI, 0.40 to 0.58;Fig 3A); estimated 24-month PFS rates were 20.5% and 1.5%. As with OS, PFS benefit with the addition of pembrolizumab was observed irrespective of PD-L1 expression (Figs 3B-3D); Data Supplement). TABLE 1. Patient Demographics and Baseline Disease Characteristics
Characteristic Pembrolizumab Combination (n = 410) Placebo Combination (n = 206)
Age, median (range), years 65.0 (34-84) 63.5 (34-84)
Male 254 (62.0) 109 (52.9)
ECOG performance status
0 186 (45.4) 80 (38.8) 1 220 (53.7) 125 (60.7) 2 1 (0.2) 0 Smoking status Former or current 362 (88.3) 181 (87.9) Never 48 (11.7) 25 (12.1) Liver metastases 66 (16.1) 49 (23.8) Brain metastases 73 (17.8) 35 (17.0) Previously treated 43 (10) 23 (11) PD-L1 TPS , 1% 127 (31.0) 63 (30.6) 1%-49% 128 (31.2) 58 (28.2) $ 50% 132 (32.2) 70 (34.0)
Could not be evaluated 23 (5.6) 15 (7.3)
Previous therapy
Thoracic radiotherapy 29 (7.1) 19 (9.2)
Neoadjuvant therapy 5 (1.2) 6 (2.9)
Adjuvant therapy 25 (6.1) 14 (6.8)
NOTE. Data are No. (%) unless otherwise indicated.
Objective Response
Confirmed objective response occurred in 197 (48.0%) patients in the pembrolizumab-combination group (com-plete response [CR], n = 4; partial response [PR], n = 193) and 40 patients (19.4%) in the placebo-combination group (CR, n = 1; PR, n = 39;Table 2). Median (range) DOR was 12.4 (1.1+ to 29.0+ months and 7.1 (2.4 to 22.0+) months in the pembrolizumab-combination and placebo-combination groups, respectively (+ indicates no progressive disease by the time of last disease assessment; Table 2). Ninety patients (52.3%) in the pembrolizumab-combination group and 8 (26.9%) in the placebo-combination group had estimated DOR$ 12 months. Response rate and DOR were higher in the pembrolizumab-combination group irrespective of PD-L1 expression (Table 2; Data Supplement).
Progression-Free Survival-2
Median (95% CI) PFS-2 was 17.0 (15.1 to 19.4) months in the pembrolizumab-combination group and 9.0 (7.6 to 10.4) months in the placebo-combination group (HR, 0.49; 95% CI, 0.40 to 0.59;Fig 4A). PFS-2 benefit associated with pembrolizumab was observed irrespective of PD-L1 expression (Figs 4B and 4C).
Outcomes in Patients With Baseline Liver or Brain Metastases
As in the overall population, an OS benefit was observed in the pembrolizumab-combination group versus the placebo-combination group in the subgroups of patients with liver (n = 115) or brain (n = 108) metastases (Figs 5A-5D). HRs for OS with pembrolizumab-combination versus placebo-combination were similar among patients with (0.62; 95% CI, 0.39 to 0.98) and without (0.58; 95% CI, 0.45 to 0.74) liver metastases (Figs 5A and 5B) and those
with (0.41; 95% CI, 0.24 to 0.67) and without (0.59; 95% CI, 0.46 to 0.75) brain metastases (Figs 5C and 5D). PFS was also improved among patients with and without liver (Data Supplement) and brain metastases (Data Supplement). Adverse Events
All-cause AEs occurred in 404 patients (99.8%) in the pembrolizumab-combination group and 200 (99.0%) in the placebo-combination group (Table 3). Grade 3-5 AEs occurred in 291 (71.9%) and 135 patients (66.8%), re-spectively. Compared with initial analysis, 2 additional patients in each group had all-cause AEs leading to death (pembrolizumab-combination: spinal fracture and general physical health deterioration, n = 1 each; total, n = 29 [7.2%]; placebo-combination: respiratory failure and bronchitis, n = 1 each; total, n = 14 [6.9%]; Data Sup-plement); 8 patients (2.0%) in the pembrolizumab-combination group died of AEs attributed to study treat-ment. AEs of acute kidney injury occurred in 25 patients (6.2%) in the pembrolizumab-combination group and occurred in 1 patient (0.5%) in the placebo-combination group. Since the prior analysis, no new patients who died as a result of the AE of acute kidney injury occurred in the pembrolizumab-combination group. The most frequently occurring AEs in both treatment groups were nausea, anemia, and fatigue (Table 3).
Immune-mediated AEs and infusion-related reactions (any grade) occurred in 107 patients (26.4%) and 26 patients (12.9%) in the pembrolizumab-combination and placebo-combination groups, respectively. Grade 3-5 immune-mediated AEs and infusion-related reactions occurred in 10.9% and 4.5%, respectively. The most frequently oc-curring immune-mediated AEs in the pembrolizumab-combination and placebo-pembrolizumab-combination groups were
Patients randomly allocated (N = 616)
Pembrolizumab plus pemetrexed and platinum
Allocated (n = 410; 66.6%)
Placebo plus pemetrexed and platinum
Allocated (n = 206; 33.4%)
Study treatment
Remaining on 1 component of allocated (n = 58; 14.1%) study therapy
Discontinued all components of allocated (n = 352; 85.9%) study therapy
Study treatment
Remaining on 1 component of allocated (n =7; 3.4%) study therapy
Discontinued all components of allocated (n = 199; 96.6%) study therapy
Subsequent therapy
Alive, no subsequent therapy (n = 8; 3.9%)a Died without subsequent therapy (n = 69; 33.5%)
1 subsequent therapy (n = 122; 59.2%) 1 subsequent PD-1 or PD-L1 inhibitor (n = 111; 53.9%) On-study cross-over (pembrolizumab) (n = 84; 40.8%)
Subsequent therapy
Alive, no subsequent therapy (n = 58; 14.1%)a Died without subsequent therapy (n = 111; 27.1%)
1 subsequent therapy (n = 183; 44.6%) 1 subsequent PD-1 or PD-L1 inhibitor (n = 55; 13.4%)
FIG 1. Disposition of patients in the study. PD-1, programmed death-1; PD-L1, programmed death-ligand 1; (a) Includes 36 patients (8.8%) in the pembrolizumab-combination arm and 4 patients (1.9%) in the placebo-combination arm who were alive without experiencing disease progression.
hypothyroidism (7.9%), hyperthyroidism (4.9%), and pneumonitis (4.9%; Table 3). Eight patients (2.0%) in the pembrolizumab-combination group experienced ne-phritis, 6 of whom had grade 3-4 events; there were no additional grade 3-4 nephritis events since the prior analysis (when 6/7 patients with nephritis had grade 3-4 events). No patients in the placebo-combination group ex-perienced nephritis.
In patients with and without liver metastases, AEs of grade$ 3 occurred in 69.2% and 72.4% of patients in the pembrolizumab-combination group, respectively, and 72.9% and 64.9% of patients in the placebo-combination group, respectively; in patients with and without brain metastases, AEs of grade$ 3 occurred in 80.0% and 70.1% of patients in the pembrolizumab-combination group, respectively, and 63.6% and 67.5% of patients in the placebo-combination group, respectively.
DISCUSSION
In this updated analysis from KEYNOTE-189, pem-brolizumab plus pemetrexed-platinum continued to show substantial improvement in OS and PFS versus placebo plus pemetrexed-platinum when administered asfirst-line therapy for metastatic nonsquamous NSCLC without sen-sitizing EGFR/ALK alterations. Median OS and PFS were approximately doubled in the pembrolizumab-combination group, and this benefit was observed in patients with both PD-L1‒positive and PD-L1‒negative disease, as well as in patients with liver/brain metastases. PFS-2 was sub-stantially improved in the pembrolizumab-combination group compared with the placebo-combination group. Safety outcomes were consistent with those from the previous interim analysis and showed that the combina-tion of pembrolizumab and pemetrexed-platinum has a manageable toxicity profile. These data support use of pembrolizumab plus pemetrexed-platinum as first-line
0 6 12 18 24 30 10 20 30 40 50 60 70 80 90 100 Time (months) OS (%) Median (95% CI) NR (20.4 to NR) 10.1 months (7.5 to NR) 12-month rate 73.3% 48.6% 24-month rate 51.9% 39.4% TPS 50% Events, n/N (%) HR (95% CI) 58/132 (43.9) 42/70 (60.0) 0.59 (0.39 to 0.88) 0 6 12 18 24 30 10 20 30 40 50 60 70 80 90 100
A
B
C
D
Time (months) OS (%) No. at risk: 114 95 85 29 0 Pembro 132 Placebo No. at risk: Pembro Placebo 70 50 34 30 11 0 No. at risk: 346 283 234 Pembro 410 Placebo 206 149 99 72 79 26 2 0 Median (95% CI) 22.0 months (19.5 to 25.2) 10.7 months (8.7 to 13.6) 12-month rate 70.0% 48.1% 24-month rate 45.5% 29.9% Total Population Pembrolizumab combination Placebo combination Pembrolizumab combination Placebo combination Pembrolizumab combination Placebo combination Pembrolizumab combination Placebo combination Events, n/N (%) HR (95% CI) 213/410 (52.0) 144/206 (69.9) 0.56 (0.45 to 0.70) 0 6 12 18 24 30 10 20 30 40 50 60 70 80 90 100 Time (months) OS (%) Median (95% CI) 17.2 months (13.8 to 22.8) 10.2 months (7.0 to 13.5) 12-month rate 63.4% 47.6% 24-month rate 38.5% 15.5% TPS < 1% Events, n/N (%) HR (95% CI) 75/127 (59.1) 51/63 (81.0) 0.52 (0.36 to 0.74) 0 6 12 18 24 30 10 20 30 40 50 60 70 80 90 100 Time (months) OS (%) 127 104 79 61 17 0 63 45 30 15 2 0 107 91 74 26 2 128 No. at risk: Pembro Placebo 58 47 29 22 11 0 Median (95% CI) 21.8 months (17.7 to 25.9) 12.1 months (8.7 to 19.4) 12-month rate 71.7% 50.0% 24-month rate 44.3% 33.0% TPS 1%-49% Events, n/N (%) HR (95% CI) 67/128 (52.3) 40/58 (69.0) 0.62 (0.42 to 0.92)FIG 2. Kaplan-Meier analysis of overall survival (OS) in the (A) overall intention-to-treat population and in subsets of patients by tumor proportion score (TPS): (B)$ 50%, (C) 1%-49%, and (D) , 1%. HR, hazard ratio; NR, not reached; pembro, pembrolizumab.
treatment of patients with metastatic nonsquamous NSCLC.
Results from this updated analysis confirm and extend those from the first interim analysis of KEYNOTE-189 (median follow-up, 10.5 months),6in which the addition of pembrolizumab resulted in significantly longer OS than chemotherapy alone (HRs for OS, 0.56; 95% CI, 0.45 to 0.70 in this analysisv 0.49 in the prior analysis). We ob-served continued OS benefit, with an estimated 2-year OS rate of 46% in the pembrolizumab-combination group versus 30% in the placebo-combination group, despite 54% of patients in the chemotherapy arm crossing over to pembrolizumab monotherapy or other PD-1/PD-L1 in-hibitors, underscoring the benefit of combining pem-brolizumab with chemotherapy as first-line treatment in advanced NSCLC. Notably, the 30% 2-year OS rate we observed in the chemotherapy alone group was high
compared with historical 2-year OS rates of 14%-19% with chemotherapy,12,13likely reflecting the effect of crossover to anti‒PD-(L)1 agents. The ongoing improvement in OS was consistent with a long-term follow-up analysis from the phase II KEYNOTE-021 cohort G study14(pembrolizumab plus pemetrexed-carboplatin v pemetrexed-carboplatin), which showed long-term survival benefit with pem-brolizumab (HR, 0.56; 95% CI, 0.32 to 0.95). Similar to OS results, this updated analysis with longer follow-up also confirmed the improved PFS and ORR observed with the addition of pembrolizumab compared with placebo in the first interim analysis of KEYNOTE-189.
Consistent with the initial analysis6and with other studies evaluating pembrolizumab monotherapy4,15,16 and com-bination therapy5 in patients with advanced/metastatic
NSCLC, the magnitude of OS, PFS, and ORR benefit
was greatest among the subgroup of patients with PD-L1 10 20 30 40 50 60 70 80 90 100 PFS (%) PFS (%) Time (months) 0 6 12 18 24 30 Time (months) 0 6 12 18 24 30 127 63 31 17 63 27 9 2 3 0 0 0 97 59 40 132 70 27 11 4 12 0 0 0 Pembro Placebo No. at risk: Pembro Placebo No. at risk: 12-month rate 25.4% 15.5% 24-month rate 9.2% 0% Median (95% CI) 6.2 months (4.9 to 8.1) 5.1 months (4.5 to 6.8) Events, n/N (%) 107/127 (84.3) 60/63 (95.2) HR (95% CI) 0.64 (0.47 to 0.89) TPS < 1% 12-month rate 47.7% 16.5% 24-month rate 32.6% 0% Median (95% CI) 11.1 months (9.1 to 14.4) 4.8 months (3.1 to 6.2) Events, n/N (%) 84/132 (63.6) 63/70 (90.0) HR (95% CI) 0.36 (0.26 to 0.51) TPS 50% 20 10 30 40 50 60 70 80 90 100 20 10 30 40 50 60 70 80 90 100
A
B
C
D
10 20 30 40 50 60 70 80 90 100 PFS (%) Time (months) 0 6 12 18 24 30 Time (months) 0 6 12 18 24 30 89 50 29 128 58 23 8 2 11 1 1 0 Pembro Placebo No. at risk: 266 149 91 410 206 No. at risk: Pembro Placebo 81 31 8 28 1 1 0 12-month rate 42.9% 17.7% 24-month rate 19.0% 3.3% Median (95% CI) 9.2 months (7.8 to 13.1) 4.9 months (4.7 to 6.9) Events, n/N (%) 95/128 (74.2) 52/58 (89.7) HR (95% CI) 0.51 (0.36 to 0.73) TPS 1%-49% 12-month rate 38.8% 16.8% 24-month rate 20.5% 1.5% Median (95% CI) 9.0 months (8.1 to 9.9) 4.9 months (4.7 to 5.5) Pembrolizumab combination Placebo combination Pembrolizumab combination Placebo combination Pembrolizumab combination Placebo combination Pembrolizumab combination Placebo combination Events, n/N (%) 304/410 (74.1) 190/206 (92.2) HR (95% CI) 0.48 (0.40 to 0.58) Total Population PFS (%)FIG 3. Kaplan-Meier analysis of progression-free survival in the (A) intention-to-treat population and in subsets of patients by programmed death-ligand 1 tumor proportion score (TPS): (B)$ 50%, (C) 1%-49%, and (D) , 1%. HR, hazard ratio; pembro, pembrolizumab.
TABLE 2. Su mmary o f Respon ses All Patients, N = 616 TPS ‡ 50%, n = 202 a TPS 1%-49%, n = 186 a TPS < 1%, n = 190 a Pembrolizumab Combination, n = 410 Placebo Combination, n = 206 Pembrolizumab Combination, n = 132 Placebo Combination, n = 70 Pembrolizumab Combination, n = 128 Placebo C ombination, n=5 8 Pembrolizumab Combination, n = 1 27 Placebo Combination, n=6 3 Best overall response CR 4 (1.0) 1 (0.5) 1 (0.8) 0 3 (2.3) 1 (1.7) 0 0 PR 193 (47.1) 39 (18.9) 81 (61.4) 17 (24.3) 6 0 (46.9) 1 1 (19.0) 41 (32.3) 9 (14.3) SD b 150 (36.6) 105 (51.0) 33 (25.0) 29 (41.4) 4 7 (36.7) 3 3 (56.9) 59 (46.5) 36 (57.1) PD 37 (9.0) 3 6 (17.5) 6 (4.5) 16 (22.9) 1 5 (11.7) 7 (12.1) 15 (11.8) 9 (14.3) Not evaluable 12 (2.9) 8 (3.9) 5 (3.8) 1 (1.4) 0 2 (3.4) 7 (5.5) 4 (6.3) No assessment 1 4 (3.4) 17 (8.3) 6 (4.5) 7 (10.0) 3 (2.3) 4 (6.9) 5 (3.9) 5 (7.9) ORR, % (95% CI) 48.0 (43.1 to 53.0) 19.4 (14.2 to 25.5) 62.1 (53.3 to 70.4) 24.3 (14.8 to 36.0) 49.2 (40.3 to 58.2) 20.7 (11.2 to 3 3.4) 32.3 (24.3 to 4 1.2) 14.3 (6.7 to 25.4) Median DOR, months (range) c 12.4 (1.1 1 to 29.0 1 ) 7 .1 (2.4 to 22.0 1 ) 15.1 (1.2 1 to 26.8 1 ) 7 .1 (3.4 to 19.4) 12.9 (2.1 1 to 29.0 1 ) 7 .6 (2.4 to 22.0 1 ) 10.8 (1.1 1 to 22.6 ) 7.8 (4.1 to 18.1 1 ) DOR $ 12 months c 90 (52.3) 8 (26.9) 40 (56.5) 4 (30.1) 2 8 (52.2) 2 (31.3) 17 (45.9) 2 (26.7) N OTE. Data are No. (%) unless otherwi se indic ated .1 indic ates no progre ssive dise ase by the time of last disease asses sment. Abb revia tions: CR, com plete respo nse; DOR , duration o f respo nse; ORR , objecti ve respons e rate; PD, progress ive disease ; PR, parti al respo nse; SD, stable dise ase; TPS , tumor propo rtion score. aEx cludes 38 patie nts fo r whom PD-L1 exp ression could not be eva luate d. bStable dise ase inclu des both stable dise ase and nonco mplete res ponse/n onpro gressiv e disease . cKa plan-Mei er estim ate.
TPS$ 50%. We also continued to observe improved OS,
PFS, and ORR among patients with PD-L1 TPS , 1%;
importantly, with longer follow-up, the 95% CI for the PFS HR did not cross 1.0 in the current analysis. The magnitude of OS and PFS benefit in patients with PD-L1 TPS , 1% (HRs [95% CI] for OS and PFS, 0.52 [0.36 to 0.74] and 0.64 [0.47 to 0.89], respectively) was notable, particularly because patients with PD-L1 TPS, 1% have a lower chance of benefit with single-agent anti‒PD-1 therapy.1,3,15,16In ad-dition, survival was improved with the addition of pem-brolizumab to chemotherapy in patients with PD-L1 TPS 1%-49%. Similar improvement in survival in this group of patients has not been observed with single-agent anti‒PD-1
therapy compared with chemotherapy.4 It has been sug-gested that improvements in outcome with regimens com-bining a checkpoint inhibitor with platinum may be due, at least in part, to induction of immunogenic cell death by platinum-based chemotherapy, which leads to recruitment of dendritic cells, downregulation of PD-L1 and PD-L2, and enhanced tumor-specific T-cell activation.17Additionally, preclinical data suggest that pemetrexed can enhance anticancer effects of immunotherapy.18Our results suggest that such mechanisms may contribute to improvements in patient outcomes.
The substantial PFS and OS benefit and 46% 2-year OS rate observed with pembrolizumab plus pemetrexed-platinum
410 336 253 185 206 No. at risk: Pembro Placebo No. at risk: Pembro Placebo No. at risk: Pembro Placebo 139 84 50 67 10 2 0 10 20 30 40 50 60 70 80 90 100 PFS-2 (%) Time (months) 0 6 12 18 24 30 12-month rate 63.6% 41.3% 24-month rate 38.4% 13.8% Median (95% CI) 17.0 months (15.1 to 19.4) 9.0 months (7.6 to 10.4) Pembrolizumab combination Placebo combination Pembrolizumab combination Placebo combination Pembrolizumab combination Placebo combination Pembrolizumab combination Placebo combination Events, n/N (%) 244/410 (59.5) 171/206 (83.0) HR (95% CI) 0.49 (0.40 to 0.59) Total Population
A
128 104 78 56 58 No. at risk: Pembro Placebo 43 24 15 23 4 2 0 10 20 30 40 50 60 70 80 90 100 PFS-2 (%) Time (months) 0 6 12 18 24 30 12-month rate 62.1% 43.1% 24-month rate 35.9% 17.5% Median (95% CI) 16.9 months (12.7 to 20.5) 9.1 months (6.8 to 13.9) Events, n/N (%) 79/128 (61.7) 47/58 (81.0) HR (95% CI) 0.59 (0.41 to 0.86) TPS 1%-49%C
127 99 65 42 63 42 23 7 14 0 0 0 10 20 30 40 50 60 70 80 90 100 PFS-2 (%) Time (months) 0 6 12 18 24 30 12-month rate 54.2% 36.5% 24-month rate 31.0% 0% Median (95% CI) 12.6 months (10.2 to 15.9) 8.9 months (6.5 to 10.5) Events, n/N (%) 88/127 (69.3) 59/63 (93.7) HR (95% CI) 0.46 (0.33 to 0.66) TPS < 1%D
132 113 93 75 70 47 33 25 26 5 0 0 10 20 30 40 50 60 70 80 90 100 PFS-2 (%) Time (months) 0 6 12 18 24 30 12-month rate 71.7% 47.1% 24-month rate 49.6% 21.3% Median (95% CI) 22.5 months (18.5 to NR) 9.9 months (7.4 to 16.4) Events, n/N (%) 62/132 (47.0) 51/70 (72.9) HR (95% CI) 0.47 (0.33 to 0.69) TPS 50%B
FIG 4. Kaplan-Meier analysis of progression-free survival-2 (PFS-2) in the (A) intention-to-treat population and in subsets of patients by programmed death-ligand 1 (PD-L1) tumor proportion score (TPS): (B)$ 50%, (C) 1%-49%, (D) , 1%. PFS-2 was defined as the time from randomization to objective tumor progression on next-line treatment (including subsequent anti‒PD-[L]1 therapy) or death from any cause, whichever occurred first. HR, hazard ratio; pembro, pembrolizumab.
in KEYNOTE-189 underscore that chemotherapy plus immunotherapy is an effective modality. Other phase III studies have evaluated immunotherapy-immunotherapy combination strategies for metastatic NSCLC. In CheckMate-227 part 1, the study coprimary endpoints were met with nivolumab plus ipilimumab versus chemotherapy (PFS in TMB-$10mut/MB: HR, 0.58; 97.5% CI, 0.41 to 0.81; P , .00119; OS in PD-L1–positive population: HR, 0.79; 97.72% CI, 0.65 to 0.96;P = .00720). In MYSTIC, the primary OS and PFS endpoints with durvalumab with and without tremelimumab versus chemotherapy were not met (PD-L1-TC-expression-$ 25% population: durvalu-mabv chemotherapy: OS HR, 0.76; 97.54% CI, 0.564 to 1.019; P = .036; durvalumab-plus-tremelimumab v
chemotherapy: OS HR, 0.85; 98.77% CI, 0.611 to 1.173; P = .202; PFS HR, 1.05; 99.5% CI, 0.722 to 1.534; P = .705).21
The OS benefit observed with the addition of pem-brolizumab occurred despite 54% (111/206) of patients in the placebo-combination group receiving subsequent anti‒PD-(L)1 therapy, including 41% (84/206) who crossed over to pembrolizumab monotherapy on-study (of 122 patients who received subsequent therapy, 91% received anti–PD-[L]1 therapy). To assess the impact of pem-brolizumab plus pemetrexed-platinum on subsequent therapy, we evaluated PFS-2, defined as the time from randomization to objective tumor progression on next-line 10 20 30 40 50 60 70 80 90 100 OS (%) 73 47 38 14 0 35 12 8 3 0 12-month rate 65.4% 34.3% Median (95% CI) 19.2 months (15.0 to 25.9) 7.5 months (4.6 to 10.0) 61 21
With Brain Metastases
Events, n/N (%) 42/73 (57.5) 28/35 (80.0) HR (95% CI) 0.41 (0.24 to 0.67) Time (months) 0 6 12 18 24 30
C
10 20 30 40 50 60 70 80 90 100 OS (%) 337 236 196 65 2 171 87 64 23 0 12-month rate 71.0% 50.9% Median (95% CI) 22.4 months (19.7 to 25.4) 12.1 months (9.1 to 15.0) 285 128Without Brain Metastases
Events, n/N (%) 171/337 (50.7) 116/171 (67.8) HR (95% CI) 0.59 (0.46 to 0.75) Time (months) 0 6 12 18 24 30
D
Time (months) 10 20 30 40 50 60 70 80 90 100 OS (%) 66 33 27 5 1 49 No. at risk: Pembro Placebo No. at risk: Pembro Placebo No. at risk: Pembro Placebo No. at risk: Pembro Placebo 11 15 4 0 12-month rate 51.0% 30.6% Median (95% CI) 12.6 months (8.1 to 19.1) 6.6 months (4.6 to 7.6) 45 26With Liver Metastases
Pembrolizumab combination Placebo combination Events, n/N (%) 43/66 (65.2) 41/49 (83.7) HR (95% CI) 0.62 (0.39 to 0.98) 0 6 12 18 24 30
A
10 20 30 40 50 60 70 80 90 100 OS (%) 344 250 207 74 1 157 84 61 22 0 12-month rate 73.6% 53.5% Median (95% CI) 23.7 months (20.1 to 25.9) 13.2 months (10.0 to 16.4) 301 123Without Liver Metastases
Pembrolizumab combination Placebo combination Pembrolizumab combination Placebo combination Pembrolizumab combination Placebo combination Events, n/N (%) 170/344 (49.4) 103/157 (65.6) HR (95% CI) 0.58 (0.45 to 0.74) Time (months) 0 6 12 18 24 30
B
FIG 5. Kaplan-Meier analysis of overall survival (OS) in patients (A) with and (B) without liver metastases and (C) with and (D) without brain metastases. HR, hazard ratio; pembro, pembrolizumab.
TABLE 3. Summary of All-Cause Adverse Events Event Pembrolizumab Combination (n = 405) Placebo Combination (n = 202)
Any Grade Grade 3-5 Any Grade Grade 3-5
Experienced$ 1 adverse event 404 (99.8) 291 (71.9) 200 (99.0) 135 (66.8)
Led to discontinuation of any treatment component 136 (33.6) 33 (16.3)
Led to deatha 29 (7.2) 14 (6.9)
Adverse events occurring in$ 15% of patients in either group
Nausea 230 (56.8) 14 (3.5) 107 (53.0) 8 (4.0) Anemia 192 (47.4) 74 (18.3) 98 (48.5) 32 (15.8) Fatigue 172 (42.5) 28 (6.9) 78 (38.6) 7 (3.5) Constipation 144 (35.6) 4 (1.0) 67 (33.2) 1 (0.5) Diarrhea 128 (31.6) 21 (5.2) 44 (21.8) 6 (3.0) Decreased appetite 120 (29.6) 5 (1.2) 64 (31.7) 2 (1.0) Neutropenia 112 (27.7) 65 (16.0) 51 (25.2) 25 (12.4) Vomiting 105 (25.9) 16 (4.0) 47 (23.3) 6 (3.0) Cough 100 (24.7) 0 61 (30.2) 0 Dyspnea 98 (24.2) 17 (4.2) 54 (26.7) 10 (5.0) Peripheral edema 88 (21.7) 2 (0.5) 29 (14.4) 0 Pyrexia 88 (21.7) 1 (0.2) 32 (15.8) 0 Asthenia 87 (21.5) 27 (6.7) 49 (24.3) 7 (3.5) Rash 87 (21.5) 8 (2.0) 26 (12.9) 3 (1.5) Thrombocytopenia 75 (18.5) 34 (8.4) 30 (14.9) 14 (6.9) Lacrimation increased 74 (18.3) 0 22 (10.9) 0 Back pain 66 (16.3) 6 (1.5) 26 (12.9) 4 (2.0)
Immune-mediated adverse eventsb 107 (26.4) 44 (10.9) 26 (12.9) 9 (4.5)
Hypothyroidism 32 (7.9) 2 (0.5) 5 (2.5) 0
Hyperthyroidism 20 (4.9) 0 6 (3.0) 0
Pneumonitis 20 (4.9) 12 (3.0) 6 (3.0) 4 (2.0)
Colitis 12 (3.0) 6 (1.5) 0 0
Infusion reactions 11 (2.7) 1 (0.2) 3 (1.5) 0
Severe skin reactions 9 (2.2) 9 (2.2) 5 (2.5) 4 (2.0)
Nephritis 8 (2.0) 6 (1.5) 0 0 Hepatitis 5 (1.2) 4 (1.0) 0 0 Hypophysitis 3 (0.7) 0 0 0 Myositis 3 (0.7) 0 0 0 Pancreatitis 3 (0.7) 2 (0.5) 0 0 Encephalitis 2 (0.5) 2 (0.5) 0 0
Type I diabetes mellitus 2 (0.5) 2 (0.5) 0 0
Adrenal insufficiency 1 (0.2) 1 (0.2) 1 (0.5) 1 (0.5)
Myocarditis 1 (0.2) 1 (0.2) 0 0
Thyroiditis 1 (0.2) 0 0 0
NOTE. Reported in all patients who received$ 1 dose of study treatment. Data are No. (%).
aEight patients (2.0%) in the pembrolizumab-combination group and 2 patients in the placebo-combination group died of adverse events attributed by the investigator to study treatment.
treatment or death from any cause, whichever occurred first.11 For the first time, we showed that first-line pem-brolizumab plus pemetrexed-platinum improved PFS-2, which was approximately doubled for patients in the pembrolizumab-combination group. This PFS-2 outcome demonstrates that treatment effects observed in the first-line setting were maintained into the next first-line of therapy. Moreover, despite the high crossover rate, we observed improved survival outcomes in patients with metastatic nonsquamous NSCLC who initiated pembrolizumab as first-line treatment in combination with chemotherapy compared with those who initiated chemotherapyfirst and then received pembrolizumab (or another anti–PD-[L]1 agent) postprogression. These results are consistent with the PFS-2 analysis for pembrolizumab monotherapy in KEYNOTE-02422 and support preferential use of pem-brolizumab in thefirst-line setting.
Liver and brain metastases are poor prognostic factors in patients with NSCLC.8,9 The efficacy of immunotherapy treatment effect in these patient populations has been uncertain, with results from one study suggesting reduced benefit in patients with liver metastases.10Consistent with poor prognosis among patients with brain or liver metas-tases, we observed shorter median OS times among these patients compared with patients without brain or liver me-tastases. However, this poorer prognosis did not diminish the treatment effect associated with the addition of pem-brolizumab to pemetrexed-platinum: HRs for OS and PFS were similar among patients with and without brain tastases and among patients with and without liver me-tastases. Outcomes in patients with liver metastases were also evaluated in the IMpower13023and IMpower15024,25 studies, which evaluated atezolizumab plus platinum-based chemotherapy versus platinum-based chemotherapy alone and atezolizumab plus bevacizumab plus platinum-based chemotherapy versus atezolizumab plus platinum-based chemotherapy versus bevacizumab plus platinum-based chemotherapy, respectively, in patients with advanced
nonsquamous NSCLC. In these 2 studies, OS benefit in patients with liver metastases was only observed among patients who received atezolizumab plus bevacizumab plus chemotherapy.
Addition of pembrolizumab to pemetrexed-platinum con-tinued to show a manageable safety profile after a mean treatment duration of 9.8 months. Despite longer follow-up with this analysis, no new safety signals were identified, including no additional immune-mediated AEs beyond those previously observed with pembrolizumab monotherapy.3,4 The proportion of patients experiencing grade 3-5 AEs was similar between the pembrolizumab-combination and placebo-combination groups, suggesting that addition of pembrolizumab to standard chemotherapy was associated with acceptable toxicity. Consistent with the primary analysis, a greater percentage of patients in the pembrolizumab-combination versus placebo-pembrolizumab-combination group experi-enced AEs of acute kidney injury and nephritis; however, despite longer treatment exposure, only 1 additional event of grade 2 nephritis occurred. AEs were generally similar between patients in the pembrolizumab-combination and placebo-combination groups across subgroups with or without liver/brain metastases.
In summary, after median follow-up of approximately 2 years, pembrolizumab plus pemetrexed-platinum resulted in substantially longer OS, PFS, and PFS-2 and a higher response compared with placebo plus pemetrexed-platinum in patients with metastatic non-squamous NSCLC without sensitizing EGFR/ALK alter-ations. Survival benefit was observed across all PD-L1 TPS groups and in patients with liver/brain metastases. Safety and tolerability results were comparable with thefirst in-terim analysis (10.5 months median follow-up). These results support pembrolizumab plus pemetrexed-platinum as a standard-of-carefirst-line therapy among patients with metastatic nonsquamous NSCLC without sensitizingEGFR/ ALK alterations, regardless of tumor PD-L1 expression. AFFILIATIONS
1Karmanos Cancer Institute, Detroit, MI
2Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
3Centre Integr ´e de Canc ´erologie de la Mont ´er ´egie, Hˆopital Charles-Le Moyne, Greenfield Park, Quebec, Canada
4Hospital Universitario Central de Asturias, Oviedo, Spain 5Vall d’Hebron University, Vall d’Hebron Institute of Oncology, Barcelona, Spain
6Hospital Universitario Fundaci ´on Jim ´enez D´ıaz, IIS-FJD, Madrid, Spain 7Westmead Hospital and University of Sydney, Sydney, New South Wales, Australia
8Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Vienna, Austria 9Southern Medical Day Care Centre, Wollongong, New South Wales, Australia
10Sanford Health, Sioux Falls, SD
11Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada 12Thoraxklinik, Heidelberg, Germany
13Soroka Medical Center, Ben-Gurion University, Beer Sheva, Israel 14Fondazione IRCCS C `a Granda Ospedale Maggiore Policlinico, Milan, Italy 15Epworth Healthcare, Richmond, Victoria, Australia
16LungenClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany
17David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA
18Department of Oncology, University of Turin, Azienda Ospedaliero-Universitaria San Luigi, Orbassano, Italy
19Hospital Universitario Quir ´onsalud Madrid, Madrid, Spain 20Chris O’Brien Lifehouse, Camperdown, New South Wales, Australia 21Kansai Medical University Hospital, Osaka, Japan
22Moffitt Cancer Center, Tampa, FL 23Merck & Co, Kenilworth, NJ
24Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milan, Italy
CORRESPONDING AUTHOR
Shirish Gadgeel, MB, BS, Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, 1500 E Medical Center Dr, 7217CC, Ann Arbor, MI 48109; e-mail: sgadgeel@med.umich.edu.
PRIOR PRESENTATION
Results presented in part at the American Association for Cancer Research Annual Meeting 2019, Atlanta, GA, March 29-April 3, 2019; and at the American Society of Clinical Oncology Annual Meeting 2019, Chicago, IL, May 31-June 4, 2019.
SUPPORT
Support for this research and for medical writing and editorial assistance was provided by Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ.
CLINICAL TRIAL INFORMATION NCT02578680
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST AND DATA AVAILABILITY STATEMENT
Disclosures provided by the authors and data availability statement (if applicable) are available with this article at DOIhttps://doi.org/10.1200/ JCO.19.03136.
AUTHOR CONTRIBUTIONS
Conception and design: Helge G. Bischoff, M. Catherine Pietanza, Marina C. Garassino
Administrative support: Helge G. Bischoff
Provision of study materials or patients: Giovanna Speranza, Enriqueta Felip, Rina Hui, Philip Clingan, Francesco Grossi, Ross R. Jennens, Edward B. Garon, Silvia Novello, Michael Boyer, Takayasu Kurata, Jhanelle E. Gray
Collection and assembly of data: Shirish Gadgeel, Enriqueta Felip, Manuel D ´omine, Rina Hui, Philip Clingan, Steven F. Powell, Susanna Yee-Shan Cheng, Helge G. Bischoff, Nir Peled, Ross R. Jennens, Martin Reck, Edward B. Garon, Bel ´en Rubio-Viqueira, Michael Boyer, Takayasu Kurata, Jhanelle E. Gray, Tuba Bas, M. Catherine Pietanza, Marina C. Garassino
Data analysis and interpretation: Shirish Gadgeel, Delvys Rodr´ıguez-Abreu, Giovanna Speranza, Emilio Esteban, Enriqueta Felip, Manuel D ´omine, Rina Hui, Maximilian J. Hochmair, Steven F. Powell, Helge G. Bischoff, Nir Peled, Francesco Grossi, Martin Reck, Edward B. Garon, Silvia Novello, Michael Boyer, Jhanelle E. Gray, Jing Yang, Tuba Bas, M. Catherine Pietanza, Marina C. Garassino
Manuscript writing: All authors Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
ACKNOWLEDGMENT
We thank the patients and their families and caregivers for participating in this study, along with all investigators and site personnel. We thank Eli Lilly and Company (Indianapolis, IN) for providing pemetrexed. Medical writing assistance was provided by Krystina Neuman, PhD, of C4 MedSolutions (Yardley, PA), a CHC Group company. Medical writing and editorial assistance was supported by Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ).
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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non–Small-Cell Lung Cancer
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer towww.asco.org/rwcorascopubs.org/journal/jco/site/ifc.
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Shirish Gadgeel
Honoraria: AstraZeneca, Merck, Genentech
Consulting or Advisory Role: Genentech, AstraZeneca, Bristol-Myers Squibb, Takeda, Xcovery, Boehringer Ingelheim, Novocure
Research Funding: Pfizer (Inst), Merck, Genentech (Inst), Merck (Inst), Blueprint Medicines (Inst), ARIAD/Takeda (Inst), Aeglea Biotherapeutics (Inst), Astellas Pharma (Inst), G1 Therapeutics (Inst), Lycera (Inst), Daiichi Sankyo (Inst)
Travel, Accommodations, Expenses: Genentech, Merck Other Relationship: AstraZeneca
Delvys Rodr´ıguez-Abreu
Consulting or Advisory Role: Roche, Bristol-Myers Squibb, MSD Speakers’ Bureau: Roche, Bristol-Myers Squibb, MSD
Travel, Accommodations, Expenses: Roche, Bristol-Myers Squibb, MSD Emilio Esteban
Travel, Accommodations, Expenses: Pfizer/EMD Serono Enriqueta Felip
Consulting or Advisory Role: Pfizer, Roche, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Guardant Health, Novartis, Takeda, AbbVie, Blue Print Medicines, Eli Lilly, Merck KGaA, Merck Sharp & Dohme, Janssen, Samsung Speakers’ Bureau: Pfizer, Roche, AstraZeneca, Bristol-Myers Squibb, Novartis, Takeda, Eli Lilly, Merck Sharp & Dohme, Medscape, Prime Oncology, Touchtime Research Funding: Fundaci ´on Merck Salud, Oncology Innovation
Other Relationship: Gr´ıfols Manuel D ´omine
Consulting or Advisory Role: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, MSD Oncology, Pfizer, Roche
Travel, Accommodations, Expenses: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Pfizer, Roche
Rina Hui
Honoraria: Merck Sharp & Dohme, Novartis, Roche, AstraZeneca, Bristol-Myers Squibb, Eli Lilly
Consulting or Advisory Role: Merck Sharp & Dohme, AstraZeneca, Roche, Bristol-Myers Squibb, Novartis, Eli Lilly
Travel, Accommodations, Expenses: Roche, Novartis Maximilian J. Hochmair
Honoraria: Boehringer Ingelheim, Takeda, MSD, BMS, AstraZeneca, Roche Steven F. Powell
Consulting or Advisory Role: Bristol-Myers Squibb (Inst)
Research Funding: Merck Sharp & Dohme (Inst), Novartis (Inst), Genentech (Inst), Incyte (Inst), Bristol-Myers Squibb (Inst), Pfizer (Inst), Vyriad (Inst), Actuate Therapeutics (Inst), AstraZeneca/MedImmune (Inst)
Susanna Yee-Shan Cheng Honoraria: Merck
Consulting or Advisory Role: Merck, AstraZeneca/MedImmune Nir Peled
Honoraria: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Pfizer, Roche, Takeda
Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche
Research Funding: MSD Oncology (Inst), Genentech (Inst), AstraZeneca (Inst), Takeda (Inst), Merck Serono (Inst), Novartis (Inst)
Travel, Accommodations, Expenses: Genentech (Inst), MSD Oncology, AstraZeneca, Pfizer (Inst)
Francesco Grossi
Consulting or Advisory Role: MSD Oncology, Bristol-Myers Squibb, AstraZeneca, Roche, Pfizer, Bayer
Speakers’ Bureau: MSD Oncology, Bristol-Myers Squibb, AstraZeneca, Roche, Pierre Fabre, Amgen, Celgene, Eli Lilly, Pfizer
Research Funding: Bristol-Myers Squibb
Travel, Accommodations, Expenses: Bristol-Myers Squibb, MSD, Roche, AstraZeneca, Pierre Fabre, Celgene, Amgen, Eli Lilly, Novartis Martin Reck
Consulting or Advisory Role: Eli Lilly, MSD Oncology, Merck Serono, Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, Celgene, Pfizer, Novartis, Genentech, AbbVie, Amgen
Speakers’ Bureau: Genentech, Eli Lilly, MSD Oncology, Merck Serono, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Pfizer, Novartis, Amgen
Edward B. Garon
Consulting or Advisory Role: Dracen, EMD Serono, Novartis
Research Funding: Merck (Inst), Genentech (Inst), AstraZeneca (Inst), Novartis (Inst), Eli Lilly, Bristol-Myers Squibb (Inst), Mirati Therapeutics (Inst), Dynavax (Inst), Iovance Biotherapeutics (Inst), Neon Therapeutics (Inst), EMD Serono (Inst)
Silvia Novello
Speakers’ Bureau: AstraZeneca, MSD, Bristol-Myers Squibb, Roche, Pfizer, Eli Lilly, Takeda, AbbVie, Boehringer Ingelheim, Bayer
Bel ´en Rubio-Viqueira
Consulting or Advisory Role: Eli Lilly, MSD Oncology, Roche Travel, Accommodations, Expenses: MSD Oncology, Roche Michael Boyer
Honoraria: AstraZeneca, Merck Sharp & Dohme (Inst), Boehringer Ingelheim (Inst), Genentech (Inst)
Consulting or Advisory Role: Merck Sharp & Dohme (Inst), AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Janssen (Inst)
Research Funding: Merck Sharp & Dohme (Inst), Pfizer (Inst), Boehringer Ingelheim (Inst), Eli Lilly (Inst), Genentech (Inst), AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Amgen (Inst), BeiGene (Inst), Ascentage Pharma (Inst), Benitec (Inst), Novartis (Inst), Janssen (Inst)
Travel, Accommodations, Expenses: Merck Sharp & Dohme, Genentech Takayasu Kurata
Honoraria: AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharma, Eli Lilly, Boehringer Ingelheim, MSD Oncology
Research Funding: MSD Oncology (Inst), AstraZeneca (Inst), Eli Lilly (Inst), Ono Pharmaceutical (Inst)
Jhanelle E. Gray
Honoraria: Eli Lilly, AstraZeneca, Celgene, Takeda, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Genentech
Consulting or Advisory Role: Celgene, AstraZeneca, Takeda, Bristol-Myers Squibb
Research Funding: Array BioPharma (Inst), Merck (Inst), AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Boehringer Ingelheim (Inst), Genentech (Inst), Novartis (Inst)
Travel, Accommodations, Expenses: AstraZeneca/MedImmune, Takeda, Boehringer Ingelheim, Eli Lilly, Celgene, Bristol-Myers Squibb Jing Yang
Employment: Merck Tuba Bas
Employment: Merck Sharp & Dohme, Fiore Healthcare Advisors (I) Stock and Other Ownership Interests: Merck Sharp & Dohme Consulting or Advisory Role: Fiore Healthcare Advisors (I)
Travel, Accommodations, Expenses: Merck Sharp & Dohme, Fiore Healthcare Advisors (I)
M. Catherine Pietanza Employment: Merck
Stock and Other Ownership Interests: Merck Sharp & Dohme
Marina C. Garassino
Honoraria: MSD Oncology, AstraZeneca/MedImmune, GlaxoSmithKline, Takeda, Roche, Bristol-Myers Squibb
Consulting or Advisory Role: Bristol-Myers Squibb, MSD, AstraZeneca, Novartis, Takeda, Roche, Tiziana Life Sciences, Sanofi-Aventis, Celgene, Daiiki Sankyo, Inivata, Incyte, Pfizer, Seattle Genetics, Eli Lilly
Speakers’ Bureau: AstraZeneca, Takeda, MSD Oncology, Celgene, Incyte, Roche, Bristol-Myers Squibb, Otsuka, Eli Lilly
Research Funding: Bristol-Myers Squibb (Inst), MSD (Inst), Genentech (Inst), AstraZeneca/MedImmune (Inst), AstraZeneca (Inst), Pfizer (Inst),
GlaxoSmithKline (Inst), Novartis (Inst), Merck (Inst), Incyte (Inst), Takeda (Inst), Spectrum Pharmaceuticals (Inst), Blueprint Medicines, Eli Lilly (Inst) Travel, Accommodations, Expenses: Pfizer, Roche, AstraZeneca No other potential conflicts of interest were reported.
